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A Review on Antioxidant Activities of Sydnone Derivatives Available online www.jocpr.com Journal of Chemical and Pharmaceutical Research, 2019, 11(10):56-67 ISSN: 0975-7384 Review Article CODEN(USA): JCPRC5 A Review on Antioxidant Activities of Sydnone Derivatives Sachin K Bhosale1*, Shreenivas R Deshpande2 and Nirmala V Shindea1 1Department of Pharmaceutical Chemistry, S. M. B. T. College of Pharmacy, Nandi hills, Dhamangaon, Tah: Igatpuri, Nashik, Maharashtra, India 2Department of Medicinal and Pharmaceutical Chemistry, HSK College of Pharmacy, BVVS Campus, Bagalkot, Karnataka, India _________________________________________________________________ ABSTRACT Mesoionic compounds are dipolar five or six membered heterocyclic compounds containing both the delocalized negative and the positive charge, for which a totally covalent structure cannot be written and which cannot be represented satisfactorily by any one polar structure. The most important member of mesoionic category of compounds is the sydnone ring system. Sydnones are mesoionic compounds having the 1, 2, 3-oxadiazole skeleton and unique variation in electron density around the ring. These characteristics have encouraged extensive study of the chemical, physical, and biological properties of sydnones, as well as their potential application as antioxidants. This chapter covers synthesis and antioxidant activity of most potent molecules having sydnone ring. Most potent antioxidant molecules are 3-(2-carboxyphenyl) sydnone, 3-(2,4-dimethoxy-5-chlorophenyl) sydnone have IC50(µM) values are 0.11 and 0.16 respectively. Similarly compounds 4-[1-oxo-3-(4-chlorophenyl)-2-propenyl]-3-(4- fluorophenyl) sydnones, 4-[1-oxo-3-(4-N-dimethylphenyl)-2-propenyl]-3-(4-fluorophenylsydnones, 4-[1-oxo-3-(4-N- dimethylphenyl)-2-propenyl]-3-(4-chlorophenyl) sydnones, 4-[1-oxo-3-(4-chlorophenyl)-2-propenyl]-3-(4- chlorophenyl) sydnones are highly potent antioxidant activity with IC50 (µM), values are 4.18, 5.12, 4.15. and 4.26 respectively. This delivers focus of future research in the development of potent antioxidant sydnone molecules. It will be used to design and development of structurally modified antioxidant sydnone derivatives to explore more potent antioxidant biodynamic molecules. Keywords: Sydnone; Mesoionic compounds; 1,2,3-oxadiazolium-5-olates.Sydnone antioxidant; Free radical scavengers _____________________________________________________________________________ 56 Sachin K Bhosale et al. J. Chem. Pharm. Res., 2019, 11(10):56-67 INTRODUCTION Causes of Oxidation Oxidants, commonly known as "free radicals," are also introduced through external sources such as exposure to the sun or pollution. Other mediums include stress, and intake of alcoholic beverages, unhealthy foods, and cigarette smoke. A poor diet also aids in the formation of free radicals [1-3]. Mechanism of Oxidants and Antioxidants Oxidative stress occurs when the production of harmful molecules called free radicals is beyond the protective capability of the antioxidant defenses. Free radicals are chemically active atoms or molecular fragments that have a charge due to an excess or deficient number of electrons. Examples of free radicals are the superoxide anion, hydroxyl radical, and transition metals such as iron, copper and nitric acid [3]. Free radicals containing oxygen, known as Reactive Oxygen Species (ROS), are the most biologically significant free radicals. ROS include the radical's [3] superoxide and hydroxyl radical, plus derivatives of oxygen that do not contain unpaired electrons, such as hydrogen peroxide, singlet oxygen, and hypochlorous acid. Because they have one or more unpaired electrons, free radicals are highly unstable. They scavenge the body to grab or donate electrons, thereby damaging cells, proteins, and DNA (genetic material) [3]. The same oxidative process also causes oils to become rancid, peeled apples to turn brown, and iron to rust. It is impossible for us to avoid damage by free radicals. Antioxidants work by donating an electron to free radicals to convert them to harmless molecules. This protects cells from oxidative damage that leads to aging and various diseases [4]. Therefore, aim of this review based on sydnone molecules possessing free radical scavenging activities are being widely proposed as bases for the development of new approaches for pharmacological regulation of oxidative-antioxidative homeostatic imbalance (Figure 1). Figure 1. Mechanism of Oxidants and Antioxidants Mesoionic Compounds In 1955 Baker, Ollis and Poole described mesoionic compounds as“a five-membered heterocycle which cannot be represented adequately by any one covalent or polar structure and have a sextet of electrons in union with the five atoms comprising the ring.” In accordance with above description, mesoionic molecules are represented by i, in which a, b, c, d, e and f atoms or groups from substituted carbon or heteroatoms. 57 Sachin K Bhosale et al. J. Chem. Pharm. Res., 2019, 11(10):56-67 b a N O + - + c e f N O d i ii b a + + - + O RN N O c e f d iii iv v Five-membered heterocyclic N-oxides and related N-imines and ylides (compound ii and iii) are not mesoionic compounds. Mesoionic compounds should be represented by structures of the type iv, but this explanation is no longer favored and the symbolism i is preferred. The large full circle and the positive sign in structure i represents delocalization of the π-electrons of the mesoionic ring in association with a partial positive charge; the exocyclic group f is associated with a corresponding partial negative charge. This polarization of the mesoionic compounds in which the ring tends towards a structure associated with a sextet of electrons led to their description as aromatic and analogy with the structure of troponev have been drawn. The original definition of mesoionic compounds comprised the possibility of six-membered mesoionic compounds but the modified definition is specifically restricted to five- membered heterocycles of type i [5]. Mesoionic compounds represent non-benzenoid aromatic heterocycle with various heteroatoms. It may be defined as “a five or six-membered heterocycle which cannot be represented satisfactorily by any one covalent or polar structure and has a sextet of electrons in association with the atoms comprising heterocyclic ring”. These are included as subclass of betaines and can be signified by a general structure derived from carbon or hetero atoms. The heterocyclic atoms bear a fractional positive charge which is balanced by a corresponding partial negative charge located on exocyclic atom or group of atoms covalently attached to the ring through a carbon atom [5,6]. A Mesoionic compound represents heterocyclic betaines having well-known range of pharmacological activities and low toxicity [1,5]. Betaines are the five membered heterocycles with an exocyclic heteroatom covalently attached to the ring through a heteroatom and not through the carbon atom. These are neutral compounds and include N-oxides, N-imides etc. Baker and Ollis in 1953, formalized some rules in order to consider a molecule as mesoionic as, it must 1) Possess a fully delocalized positive and negative charge. 2) Be planar and have a five-membered heterocyclic ring with an exocyclic atom or group which is capable of bearing negative charge density. 3) Possess substantial resonance energy. The above characteristics clearly distinguish mesoionic systems from formally related dipolar species such as zwitter ions and ylides. Such species have some degree of charge fixation whereas the mesoionic systems contain delocalized charges. In the structure of sydnone ring, N (2) possesses positive character and C (4) is negative with both nucleophilic and acidic character [7]. 58 Sachin K Bhosale et al. J. Chem. Pharm. Res., 2019, 11(10):56-67 Sydnones Earl and Mackney in 1935, reported that “treatment of N-nitroso-N-phenylglycine (R=H) with acetic anhydride gave a neutral, anhydro derivative to which the bicyclic structure was assigned.” It was found to have general utility and thus various analogues of the compound were synthesized as “sydnone”. In mesoionic systems, charge distribution is delocalized, not a single resonance form can be drawn accurately. Sydnones are a group of 1, 2, 3-oxadiazoles that are cyclic in nature (Figure 2) [5,6]. Figure 2. Mesoionic structure of sydnone Physicochemical Properties and Electronic Structure Sydnones are unique nitrogenous compounds and chemically 1, 2, 3-oxadiazolium-5-olates (1). These are nonbenzenoidheteroatomicmesoionic molecules and can be represented in dipolar canonical formulas [5,6]. + R' N R N O O Sydnones are pseudo-aromatic heterocyclic compounds, which are dipolar, bearing a unique variation of electron cloud around the ring. These compounds are stable with substantial polarity and are isolated as crystalline solids. Generally, aryl sydnones occur as solid crystals whereas alkyl sydnones appear to be either liquids or solids with low melting point. Sydnones are readily soluble in polar organic solvents but insoluble in water and are stable at room temperature. Wang and co-workers recommended that “Electrons of π bond of sydnones are unequally delocalized”. Further study proved that N2 and N3 are neutral; C4, O1 and O6 are negatively charged whereas C5 was positively charged. They also stated that “There occurs little resonance interaction between sydnone ring and N3 phenyl group” [7] (Figure 3). 59 Sachin K Bhosale et al. J. Chem. Pharm. Res., 2019, 11(10):56-67 Substitution on C4 Aromatic substitution 4 O- 3 5 R N+ O1 N Sydnone ring 2 Substitution on
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